Integrin function is intimately linked to many facets of lung biology including morphogenesis, inflammation, remodeling in the setting of injury, and tumor progression. Although the expression pattern and ligand specificity Of integrin heterodimers is well defined, regulation Of integrin function is much less well understood. Recent studies indicate that the function of a set of beta 1 and 2 integrins is regulated by the urokinase receptor (uPAR), a glycolipid-anchored non-integrin membrane protein. These studies reveal that uPAR, integrins, and a third membrane protein caveolin form a tri-partite complex which regulates integrin signaling. The recent identification of a uPAR binding site on the o' chain of the 132 integrin Mac-I (cDI lb1CDI8) verifies the direct association of uPAR with integrins and provides new insight into how integrins partn,er with other membrane proteins. On the basis of these recent studies it is proposed that BAR and caveolin promote 13land 132 integrin function by coordinately regulating Src family kinase activation during ligand engagement by these adhesion receptors Experiments are proposed to define further the interaction site between uPAR and Mac-I and use this information to loca1ize a binding site on 131 integrins. A goal of this line of experiments is to identify peptide-based reagents which disrupt uPARIintegrin/caveolin complexes. Caveolindeficient epithelial cells with defective 131 integrin signaling will be transfected with caveolin mutants and isotypes to elucidate mechanisms underlying caveolin's role in integrin regulation. The capacity of uPAR to regulate tyrosine kinases and phosphatases surrounding integrins will be tested in these cells and in macrophages. Reagents disrupting integrin/caveolin complexes will be used in murine models of neutrophil, monocyte, and eosinophil pulmonary inflammatory responses in vivo. The goals of the application are to understand the basic mechanisms through which uPAR and caveolin interact with and modify the signaling capacity of integrins and to determine whether agents which inhibit these interactions have the potential to regulate integrin function in vivo. Results of these experiments could provide a novel approach to regulation of integrin function in the setting of disease.